This invention relates to a novel synergistic combination of prostaglandin compounds used to induce menses and interrupt early pregnancy in female primates, particularly humans. This invention further provides compositions to be used in this method.
The prostaglandins are derivatives of prostanoic acid which has the structure and carbon atom numbering as shown in formula I. The prostaglandins combined in the present invention are those of the 9-deoxo-9-methylene E series, having the substituents on the cyclopentane ring as shown in formula II, and those of the F.alpha. series, having the substituents on the cyclopentane ring as shown in FIG. III. For a fuller discussion of the prostaglandins see e.g., Bergstrom et al. Pharmacol. Rev. 20:1 (1968), and references cited therein. For a fuller discussion of prostaglandin nomenclature see, e.g., N. A. Nelson, Journal of Medicinal Chemistry, 17:911 (1974).
The prostaglandins are useful for a wide variety of pharmacological purposes. Thus compounds of the F.alpha. series are useful in stimulating smooth muscle, inhibiting gastric secretion, decongesting nasal passages, decreasing blood platelet adhesion, and for a wide variety of purposes in reproductive medicine, e.g., labor induction, abortion, cervical dilation, regulation of the estrus, and regulation of the menstrual cycle. Compounds of the E series are useful in stimulating smooth muscle, affecting lipolytic activity, inhibiting gastric secretion, controlling spasms and facilitating breathing in asthmatic conditions, decongesting nasal passages, decreasing blood platelet adhesion, and for a wide variety of uses in reproductive medicine, e.g., labor induction, abortion, cervical dilation, regulation of the estrus, and regulation of the menstrual cycle.
The present invention is concerned with the use of prostaglandins for menses induction. More particularly, the present invention relates to menses induction accompanied by pregnancy termination. Thus, the phrases "menses induction", "induction of menses", and the like are meant to include pregnancy termination if the subject is pregnant.
While a number of prostaglandins have been shown to be effective luteolytic agents in various animal tests, it is difficult to find a prostaglandin which is 100% effective in inducing menses in female primates with little or no toxicity or side effects. ("Luteolytic" agents are those which cause corpus luteum regression. A functional corpus luteum is essential in early pregnancy).
It has been demonstrated that combinations of certain prostaglandins of the F series and the E series are effective in inhibiting nidation (implantation of the ovum) in rats and hamsters, as disclosed in U.S. Pat. No. 3,978,229. However, the teachings of the prior art are of limited value in assessing the existence of primate luteolytic activity in that it is not possible to predict accurately the luteolytic activity of a prostaglandin combination in primates using rodent data. See e.g., "The Use of PG's in Human Reproduction", Population Reports, Population Information Program, The Johns Hopkins University, Prostaglandins, Series G, No. 8, (March 1980); and J. W. Wilks, "A Procedure for Evaluating Luteolytic Agents in Primates", Ovarian Follicular And Corpus Luteum Function C. P. Channing, et al., Eds., pp. 757-766 (Plenum Press, New York 1979).
Various control mechanisms exist governing corpus luteum function in mammalian species. The uterus apparently regulates corpus luteum function in infraprimate animals, but the role of the uterus in primate luteal function has not been established. Thus, while PGF.sub.2 .alpha., a physiologic luteolytic substance of uterine origin, has been successfully employed to regulate estrous cycles of domestic animals (J. W. Lauderdale, et al., J. Anim. Sci. 38:964 (1974)), it was ineffective in controlling the human corpus luteum (W. J. LeMaire, et al., Prostaglandins 1:259 (1972)).
An effective luteolytic method of inducing menses in females must be able to counteract the corpus luteum stimulating effects of chorionic gonadotropin. Agents which have been shown to be effective during nonfertile menstrual cycles have been ineffective during early gestation and in nonpregnant women given exogenous human chorionic gonadotropin (hCG). See, e.g. J. W. Wilks, supra, and references cited therein.
An additional problem with the prior art combinations is the acute toxicity of some of the prostaglandins employed therein. For example, 16,16-dimethyl PGE.sub.2 is part of the most potent luteolytic combination disclosed in U.S. Pat. No. 3,978,229. (The other prostaglandin is 15(S), 16(R)-dimethyl PGF.sub.2 .alpha.). However, the "synergistic" combination employed in the rat included 250 .mu.g/kg of body weight of 16,16-dimethyl PGE.sub.2, which is very toxic in primates, causing convulsions and death at doses as low as 100 .mu.g/kg of body weight.
It has surprisingly and unexpectedly been found that the prostaglandin combinations of the present invention produce a synergistic menses inducing effect in female primates. These synergistic prostaglandin combinations are virtually 100% effective using low doses of the compounds, essentially without side effects.